An elevated concentration of reducing sugars (i.e., glucose) in the blood and in the intracellular environment of an animal, namely a human, typically results in the nonenzymatic formation of glycation and dehydration condensation complexes known as advanced glycation end-products (AGE). These AGE complex products form on free amino groups, on proteins, on lipids and on DNA (Bucala and Cerami, Adv Pharmacol 23:1-34, 1992; Bucala et al., Proc Natl Acad Sci 90:6434-6438, 1993; Bucala et al., Proc Natl. Acad Sci 81:105-109, 1984). This phenomenon is called “browning” or a “Maillard” reaction and was discovered early in this century by the food industry (Maillard, Ann Chim 5:258-317, 1916). The significance of a similar process in biology became evident only after the discovery of the glycosylated hemoglobins and their increased presence in diabetic patients (Rahbar, Clin Chim Acta 20:381-5, 1968; Rahbar et al., Biochem Biophys Res Commun 36:838-43, 1969). A diabetic patient's AGE level increases markedly as a result of sustained high blood sugar levels and often leads to tissue damage through a variety of mechanisms including alteration of tissue protein structure and function, stimulation of cellular responses through AGE specific receptors and/or the generation of reactive oxygen species (ROS) (for a recent review see Boel et al., J Diabetes Complications 9:104-29, 1995). These AGE have been shown to cause complications in patients suffering from various pathological conditions, including, but not limited to, diabetes mellitus, rheumatoid arthritis, Alzheimer's Disease, uremia and in atherosclerosis in persons undergoing hemodialysis.
Advanced glycation end-products bind to cell surface receptors on a variety of cells including, but not limited to, endothelial cells of the microvasculature, monocytes and macrophages, smooth muscle cells, mesengial cells and neurons through a specific receptor for AGEs, termed RAGE. RAGE is a member of the immunoglobulin super family of cell surface molecules. Increased levels of RAGE are expressed in a number of tissues including, but not limited to, aging tissues, diabetic tissues, the vasculature and the kidney. Activation of RAGE has been implicated in a variety of conditions including, but not limited to, acute and chronic inflammation, in certain complications of diabetes, nephropathy, atherosclerosis and retinopathy, Alzheimer's disease, erectile dysfunction and in tumor invasion and metastases.
The complications associated with each of these aforementioned pathological conditions places a significant burden on afflicted patients. Moreover, these complications have detrimental effects on society in general. As one example, the global prevalence of diabetes mellitus afflicts millions of individuals resulting in significant increases of morbidity and mortality rates. These increased morbidity and mortality rates, together with the great financial burden of treating diabetic complications, are major incentives to search for and develop medications having the potential of preventing or treating complications of the disease.
Certain medications have been developed that inhibit the nonenzymatic formation of glycation and dehydration condensation complexes in patients with the above-mentioned pathological conditions. U.S. Pat. No. 6,337,350, to Rahbar et al., discloses derivatives of aryl and heterocyclic ureido and aryl and heterocyclic carboxamido phenoxyisobutyric acids and of benzoic acid, which have been found to inhibit the nonenzymatic glycation of various proteins. Many other phenoxyisobutyric acid derivatives, as well as certain other compounds, are also disclosed that have similar beneficial effects. While it is beneficial to have these medications available for treatment, other health-related and/or disease related treatment concerns exist.
It is not uncommon for a patient suffering from multiple ailments and/or diseases to require disease specific treatment(s). If a patient is taking a specific medication treatment regime for a disease(s) (i.e., if the patient is taking at least one medication for each disease and/or more than one medication for at least one disease), this poses significant medication administration issues that must be overcome if the patient is to receive a therapeutic amount of a medication for the acquired disease(s). These issues include, but are not limited to, potential drug-drug interactions. Most often, these drug-drug interactions occur in the alimentary canal. These medication administration issues become even more complicated if the above-mentioned patient is to receive a therapeutic amount of a medication at predetermined time interval(s). Therefore, it may be necessary to deliver the medication via a parenteral route of administration or via a medical device (i.e., a medication releasably applied to a medical device, a medication releasably applied to a coating on a medical device and/or absorbed/adsorbed into or onto a coating or other surface that is either part of the medical device and/or applied to the medical device) to minimize and/or alleviate these medication administration issues. However, non-parenteral routes of administration are also acceptable, but a patient's complete medication profile must be contemplated to determine whether any potential drug-drug interactions exist.
In light of various patient specific factors, administration of these medicaments remains challenging. Moreover, administration of these medications has not been achieved in conjunction with a medical device prior to applicant's discovery. Applicant has surprisingly discovered effective methods of administration of these medications and also discovered medication releasing medical devices, wherein at least a portion of the medical device releasably includes, or is releasably coated with, medication(s) that inhibit the nonenzymatic formation of glycation and dehydration condensation complexes known as advanced glycation end-products.